Chin Maguire, Hannah Cantrill
BOX 1 PROSPERO registration
Review question(s)
How safe and effective is nebulised HS solution when used to treat acute bronchiolitis in hospitalised infants (under the age of 2 years).
Searches
The following electronic databases will be searched: MEDLINE (via Ovid) (1946 to January 2015), EMBASE (1974 to January 2015), the Cochrane Central Register of Controlled Trials, Google Scholar (2010 to January 2015) and Web of Science (2010 to January 2015). The full search strategy used in each database is available inAppendix 6. No restrictions or limits (e.g. age, language or publication date) will be applied in any of the databases other than Google Scholar where a restriction of 2010 onwards will be applied.
Trial registries: other than electronic databases, individual trial registries were searched using the terms ‘bronchiolitis’and‘hypertonic saline’. These included: ClinicalTrials.gov; UK Clinical Trials Gateway; Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database, HTA Database); controlled-trials.com; centrewatch.com and National Research Register, to identify any unpublished data.
Journals: the major journals identified for hand searching are Chest, Paediatrics, and Journal of Paediatrics because these are the journals where the current articles of choice were found. Each of the journals will be searched using the terms‘hypertonic saline’and‘bronchiolitis’.
Other searches: the reference lists of all identified and suitable trials will be checked to identify any further trials with a view to obtaining any published data in order to minimise publication bias.
Types of study to be included
Published and unpublished, RCTs and quasi-randomised trials; cohort and other observational studies will be excluded.
Only trials which have completed recruitment will be included in the review.
No language or publication restrictions will be applied at the search stage however only those trials published in English will be included in the review.
Condition or domain being studied
Bronchiolitis (also known as RSV) is a very common respiratory tract infection in young children, most commonly aged between 2 and 5 months. Acute bronchiolitis results in symptoms of swelling of the airway wall, increased mucous production and an impairment of secretion clearance causing airway obstruction and a combination of gas trapping and ineffective gaseous exchange. Acute bronchiolitis is widely accepted to refer to the first episode of acute wheezing in infants younger than 24 months which may start as an upper respiratory tract viral infection. Overall, 1–2% of children diagnosed with bronchiolitis will require hospitalisation. Bronchiolitis is the main cause of hospital admission for respiratory tract infections with
recurrent wheezing episodes seen in up to 50% of severely infected children years after their primary diagnosis. Participants/population
Research with children up to the age of 2 years who had been hospitalised as the result of an episode of acute bronchiolitis will be considered for the review. Criteria for inclusion include a first episode of acute wheezing associated with bronchiolitis. Not all cases of bronchiolitis are a result of RSV and as such all cases of bronchiolitis regardless of organism will be included.
Intervention(s), exposure(s)
The intervention under consideration is nebulised HS with or without an adjunct treatment given versus NS or no intervention (control). These can be summarised in the following groups:
1. Nebulised HS alone vs. NS
2. Nebulised HS plus a bronchodilator (e.g. salbutamol) vs. NS
3. Nebulised HS plus a bronchodilator (e.g. salbutamol) vs. NS plus same bronchodilator 4. Nebulised HS alone or plus a bronchodilator (e.g. salbutamol) vs. no intervention
No restrictions will be applied in terms of the concentration, dose or the way the intervention (HS) or control (NS with or without adjunct treatment) is administered in the trials.
Comparator(s)/control
Please seeIntervention(s), exposure(s)above for outline of comparators used in the review. Context
Studies will not be excluded based on the outcomes they measure; only the population and intervention will be used to screen trials for the review.
A systematic review by Zhanget al.conducted in 2010 suggests that HS results in improved clinical outcomes for infants with viral bronchiolitis. The review looked at children in a number of different settings (hospitalised, outpatients and those in the emergency department). This review will update the systematic review conducted in 2010 (with respect to hospitalised infants only) to incorporate both new published and unpublished data from recent clinical trials conducted since 2010.
Outcome(s) Primary outcomes
The primary objective of this review is to determine whether or not nebulised HS results in benefits to hospitalised children in terms of reducing the LoS typically defined as time to meeting discharge criteria. A‘summary of findings’table will be included in the results section. For any dichotomous outcomes results will be expressed as risk ratios and 95% CI. For any continuous outcomes the MD and 95% CI will be used. Secondary outcomes
Secondary outcomes of interest include rate of readmission to hospital; any AEs however described but particularly tachycardia, hypertension, pallor, tremor, nausea, vomiting and acute urinary retention; and final CSS scores. Data extraction (selection and coding)
The titles and abstracts of all the studies identified by the search will be performed. The full articles of any studies that appear to meet the inclusion criteria or those where it is unclear, or where there is insufficient information to make a decision for their inclusion, will be retrieved. Papers that do not meet the inclusion criteria will be excluded.
Data will be extracted onto a standardised data extraction form to both assess the methodological quality of the studies and retrieve outcome data.
1. Key data to be extracted include: 2. study overview (country, year)
3. participant characteristics (age, number randomised, baseline imbalances assessed by the authors in trials, withdrawals, per cent allocated completing follow-up, illness severity, eligibility)
4. intervention and control group details (number randomised in each group, intervention details: duration, delivery, other drugs and compliance)
5. Outcomes data:
i. for continuous outcomes: LoS, typically defined as time to meeting discharge criteria (mean LoS typically defined as time to meeting discharge criteria, SD and number of patients in each group, measured by who); and CSS (mean final CSS score, SD, number of patients for both groups). Principal summary measure is weighted MD in LoS typically defined as time to meeting discharge criteria
6. qualitative AE data as available.
Risk of bias (quality) assessment
Risk of bias assessment will be performed on the extracted data based on the Cochrane Collaboration’s recommendations to assess the quality of the studies. Data will be summarised in the‘risk of bias’tables in the results of the review. Trials will be graded on their quality as‘A’low risk of bias,‘B’high risk of bias or‘C’risk of bias unclear. Where a‘C’grading is given, every effort will be made to obtain further information to categorise the trial by contacting the trial authors within the specified time frame of this piece of work. The funnel plot method will be used to investigate whether or not publication bias is present if sufficient studies are included in the meta-analysis. Any unpublished results that are obtained will be incorporated.
Risk of bias assessment data items will include: sequence generation; allocation concealment; blinding (outcome and personnel); incomplete outcome data and selective reporting
Data will be input into RevMan to generate summary statistics. Strategy for data synthesis
The primary outcome data collected are the LoS typically defined as time to meeting discharge criteria SD and number of participants in both intervention and control groups. A FE model will be used to analyse these continuous data based on the assumption that LoS typically defined as time to meeting discharge criteria outcome would estimate the same effect size in each of the studies.153A weighted MD and associated 95% CI
will be calculated (via RevMan) in order to generate a forest plot. The FE model allows the studies to be weighted depending on their sample size; the greater the sample size, the greater the weight assigned to the trial.
The secondary outcomes of interest include AEs (however reported), rates of hospital readmission and final CSS score. Data on AEs will be collected (however these are defined) and a descriptive narrative of the results will be undertaken. These form part of the qualitative synthesis of the results.
Analysis of subgroups or subsets None planned.
Dissemination plans
The review will form part of the HTA monograph for the SABRE clinical trial. Contact details for further information
Chin Maguire
ScHARR, University of Sheffield [email protected]
Organisational affiliation of the review
ScHARR, University of Sheffield, 30 Regent Street, Sheffield S1 4DA, UK. Review team
Mrs Chin Maguire, Clinical Trials Unit, University of Sheffield; Miss Hannah Cantrill, Clinical Trials Unit, University of Sheffield, Sheffield, UK.
Collaborators
Dr Daniel Hind, ScHARR, University of Sheffield, Sheffield, UK. BOX 1 PROSPERO registration (continued)
Details of any existing review of the same topic by the same authors None.
Anticipated or actual start date 1 January 2013.
Anticipated completion date: 25 April 2014. Funding sources/sponsors
The results of the systematic review will be presented in the monograph for the‘SABRE (hypertonic Saline in Acute Bronchiolitis RCT and Economic evaluation)’trial funded by the HTA, reference 09/91/22.
Conflicts of interest None known.
Other registration details None.
Language English. Country England.
Subject index terms status Subject indexing to be assigned. Subject index terms
Bronchiolitis; humans; infant; saline solution, hypertonic. Reference and/or URL for protocol
None available. Stage of review Ongoing.
Date of registration in PROSPERO 3 March 2014.
Date of publication of this revision 18 December 2014.
Stage of review at time of this submission Started Completed
Preliminary searches No Yes
Piloting of the study selection process No Yes Formal screening of search results against eligibility criteria No Yes
Data extraction Yes No
Risk of bias (quality) assessment Yes No
Data analysis Yes No